Identification of a novel tumor-associated antigen, cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers.
OBJECTIVE
To establish cancer immunotherapy, it is important to identify the tumor-associated antigens (TAA) that are strongly expressed in the tumor cells but not in the normal cells. In this study, to establish an effective anticancer immunotherapy, we tried to identify the useful TAA of pancreatic cancer.


METHODS
Based on a previous genome-wide cDNA microarray analysis of pancreatic cancer, we focused on cadherin 3 (CDH3)/P-cadherin as a novel candidate TAA for anticancer immunotherapy. To identify the HLA-A2 (A*0201)-restricted CTL epitopes of CDH3, we used HLA-A2.1 (HHD) transgenic mice (Tgm). Furthermore, we examined the cytotoxicity against the tumor cells in vitro and in vivo of CTLs specific to CDH3 induced from HLA-A2-positive healthy donors and cancer patients.


RESULTS
CDH3 was overexpressed in the majority of pancreatic cancer and various other malignancies, including gastric and colorectal cancers, but not in their noncancerous counterparts or in many normal adult tissues. In the experiment using HLA-A2.1 Tgm, we found that the CDH3-4(655-663) (FILPVLGAV) and CDH3-7(757-765) (FIIENLKAA) peptides could induce HLA-A2-restricted CTLs in Tgm. In addition, peptides-reactive CTLs were successfully induced from peripheral blood mononuclear cells by in vitro stimulation with these two peptides in HLA-A2-positive healthy donors and cancer patients, and these CTLs exhibited cytotoxicity specific to cancer cells expressing both CDH3 and HLA-A2. Furthermore, the adoptive transfer of the CDH3-specific CTLs could inhibit the tumor growth of human cancer cells engrafted into nonobese diabetic/severe combined immunodeficiency mice.


CONCLUSIONS
These results suggest that CDH3 is a novel TAA useful for immunotherapy against a broad spectrum of cancers, including pancreatic cancer.
Imai
Katsunori
K
Department of Immunogenetics and Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.
Hirata
Shinya
S
Irie
Atsushi
A
Senju
Satoru
S
Ikuta
Yoshiaki
Y
Yokomine
Kazunori
K
Harao
Michiko
M
Inoue
Mitsuhiro
M
Tsunoda
Takuya
T
Nakatsuru
Shuichi
S
Nakagawa
Hidewaki
H
Nakamura
Yusuke
Y
Baba
Hideo
H
Nishimura
Yasuharu
Y
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D019264:Adoptive Transfer; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D000939:Epitopes / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D015789:HLA-A2 Antigen / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D016086:Lentivirus; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
C512197:CDH3 protein, human; D015820:Cadherins; D000939:Epitopes; D015789:HLA-A2 Antigen; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger